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Two tapered statistical copolymers were prepared by the oxyanionic polymerization of ethylene oxide and propylene oxide and characterized by gel permeation chromatography and 13C NMR spectroscopy. We denote the copolymers t-E/P38 and t-E/P30, where E = oxyethylene, OCH2CH2, and P = oxypropylene, OCH2CH(CH3), and the number denotes the mole percentage P. In each case the copolymer chain length was ca. 100 oxyalkylene units. The association of the copolymers to form micelles in aqueous solution was checked by dynamic light scattering. The critical micelle temperatures (cmt) of the copolymers at several concentrations were determined by static light scattering and dye solubilization, and values of the apparent standard enthalpy of micellization (DeltamicHapp0) were obtained. For both copolymers, a low value of DeltamicHapp0 was found when the copolymer concentration exceeded ca. 150 g dm(-3).
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PMID:Thermodynamics of micellization of tapered statistical copolymers of ethylene oxide and propylene oxide in water. 1517 71

An application of Fourier transform infrared (FT-IR) spectroscopy equipped with an attenuated total reflectance (ATR) probe for in-line monitoring of a hydrochloride (HCl) salt formation process of 4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluorometryl)phenyl]-1H-imidazol-5-yl}-N-[(1S)-1-phenylethyl]pyridine-2-amine (freebase), an active pharmaceutical ingredient as a P38 MAP kinase inhibitor, is described. The freebase forms both mono- and bis-HCl salts due to its structural features. The mono-HCl salt is the desired product but the bis-salt is an impurity. The key to maximizing the product yield and minimizing the impurity level is to monitor the salt-forming reaction and to terminate it at the correct HCl charge amount. The process analytical technology (PAT) provided real-time data for process control and overcame the limitations that had been previously encountered by other analytical instrumentations, such as high-performance liquid chromatography and titration. Two qualitative approaches for reaction endpoint determination were employed. In the first approach, changes in the concentration of the freebase and bis-salt were monitored via the first derivative concentration profiles. The flat point in the freebase profile and the rise in the bis-salt profile were used as a detection bracket for the endpoint of HCl charging. In the second approach, principal component analysis (PCA) was used to classify the status of the process based on a spectral library consisting of spectra collected around the endpoint. Results indicated that both methods provided adequate accuracy for endpoint control in a small window between 1.0 and 1.05 HCl to freebase mole ratio. Both methods were used to support a scaled up process. Three batches of MAP mono-HCl salt formation were successfully controlled and prepared.
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PMID:Real-time endpoint monitoring and determination for a pharmaceutical salt formation process with in-line FT-IR spectroscopy. 1632 95

Most giant congenital melanocytic nevi (GCMN) exhibit an activating mutation in NRAS. Constitutive activation of the RAS-ERK signaling pathway induces proliferation in nevus cells and plays a pivotal role in melanoma development. In this study, we studied the efficacy of RAS-ERK pathway targeted therapy in GCMN. We isolated nevus cells from GCMN (GNCs) and compared the morphology of GNCs with normal melanocytes and the A375 melanoma cell line. Proliferation curves of GNCs and A375 cells were determined using Cell Counting Kit-8 assays. Cell cycle distribution was measured using flow cytometry. The RAS-ERK pathway inhibitors Vemurafenib and Trametinib, which are used in melanoma therapy, were applied. After inhibitor treatment, GNCs were analyzed for apoptosis and the protein expression of ERK, p-ERK, P38, p-P38 and P53. We found that compared with A375 cells, the cultured GNCs exhibited a higher G1 phase population and a lower proliferation rate. Both Vemurafenib and Trametinib treatment induced GNCs apoptosis in a dose-dependent manner, with Vemurafenib having a stronger effect. With inhibitor treatment, ERK activation was greatly suppressed, while the expression of p-P38 exhibited no obvious change. Vemurafenib treatment also increased the level of P53 protein in GNCs. These findings suggested that Vemurafenib treatment may be a potential therapeutic strategy for treatment of GCMN via targeting of the RAS-ERK pathway.
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PMID:Therapeutic effects of targeting RAS-ERK signaling in giant congenital melanocytic nevi. 2973 11